Genetic disorders

Question 1

What are the main points for using a genetic pedigree?

Answer 1

Provides a clear simple summary of information
Able to spot patterns easily
Explain pattern to patient
Calculate the risk of passing on disease or being a carrier
Allows informed choice

Question 2

How are generations denoted on genetic pedigree?

Answer 2

Using roman numerals

Question 3

How are offspring birth ordered traditionally on genetic pedigrees?

Answer 3

Left tor right, individuals denote by Arabic numerals.

Question 4

Conventionally, which side is paternal lineage and maternal lineage denoted on a genetic pedigree?

Answer 4

Paternal - right

Maternal - left

Question 5

In relation to the proband which % of DNA is shared between grandparents?

Answer 5

25%

Question 6

In relation to the proband, which % of DNA is shared between parents?

Answer 6

50%

Question 7

In relation to the proband, which % of DNA is shared between siblings?

Answer 7

50%

Question 8

In relation to the proband, which % of DNA is shared between Aunts & uncles?

Answer 8

25%

Question 9

In relation to the proband, which % of DNA is shared between 1st degree cousins?

Answer 9

12.5%

Question 10

What is classified as consanguineous mating?

Answer 10

Mating occurs if 2nd cousins or closer (3.13% shared DNA)

Question 11

What pattern is provided by autosomal dominant conditions on a genetic pedigree?

Answer 11

Vertical transmission
The tendency for not all offspring expressing the conditions
Both genders are affected
Minimum of one parent required.

Question 12

Why are some familial disorders not expressed within the pedigree?

Answer 12

Have an age of onset, developing with age due to an accumulation of sporadic mutations
Decreased patients may not develop the disease, thus not expressed within the pedigree

Question 13

Which trinucleotide repeat causes Huntington’s?

Answer 13

CAG

Question 14

What inheritance pattern is demonstrated by Huntington’s?

Answer 14

Monogenic autosomal dominant disorder

Unstable mutation confers for a variable number of repeats

Question 15

How many CAG repeats cause full penetrance?

Answer 15

40+

Question 16

Why is the Huntingtin gene unstable?

Answer 16

Instability increases over successive generations. CAG is a codon for gutamine, series of repeats results in the production of glutamine chain -Polyglutamine tract/Poly-Q tract
Accumulation of HTT within neurones results in neuronal death
Age of onset decreases with severity and number of repeats

Question 17

What type of gene is MEN1?

Answer 17

Tumor suppressor
Affected individuals have one mutation in one allele, over a period of time, second version is mutated, thus there is no active version

Question 18

The development of a second mutation within the MEN1 gene causes what?

Answer 18

Leads to the development of benign adenomas

Question 19

How is mitochondrial inheritance conferred?

Answer 19

The mutated gene is present in the mitochondrial DNA of the ovum; subsequent.y mtDNA is exclusively inherited from maternal lineages

Question 20

Which lineage has a strong inheritance pattern of mitochondrial DNA?

Answer 20

Maternal lineage

Question 21

What type of transmission pattern is evident for mitochondrial DNA inheritance?

Answer 21

Vertical transmission

Affects all generations,both genders are affected since the mutated gene is inherited from the mother

Question 22

What are the complicating factors of mitochondrial inheritance in terms of genomes and mt number?

Answer 22

Have multiple copies of genome ,therefore a proportion express normal genotype and mutant genotype
Offspring inherit varying numbers of mutated mitochondria this can change with time

Question 23

What is the pattern of inherited mitochondrial disease and age? Explain

Answer 23

Diseases develop with age due to accumulation of mutated mitochondria

Question 24

How do mitochondria replicate?

Answer 24

Binary fission

Question 25

What is the definition of genetic risk?

Answer 25

Risk is the calculation of the predicted chance of having the disease or being a carrier Risk can only be calculated based upon the known phenotype to subject Multiplication of risks to calculate overall risk of inheriting genetic disorder

Question 26

What are risk modifiers in terms of phenotypic advantage?

Answer 26

The lineages of the disease prevalence (maternal or paternal); X-linked and mitochondrial inheritance patterns Ethnic background: Diseases have different prevalence in different populations Example: CF, Sickle cell, Tay-Sachs Whereby the heterozygous express a phenotypic advantage within the environment, the allelic frequency would increase within areas of relatively higher selection pressure Founder effect

Question 27

What is the founder effect?

Answer 27

Due to a genetic bottleneck, also produced sub-populations with increased prevalence

Question 28

Which inheritance pattern is demonstrated by hereditary hemochromatosis?

Answer 28

Autosomal recessive disorder

Question 29

Which protein is the hereditary hemochromatosis allele affecting?

Answer 29

Homeostatic iron regulatory protein (HFE)

Question 30

What effect happens due to dysfunctional HFE protein?

Answer 30

Excess iron absorption

Question 31

Where is the HFE protein located?

Answer 31

Cell surface membrane of hepatocytes

Question 32

Which receptor is the HFE protein associated with?

Answer 32

Transferrin receptor i

Question 33

Which plasma protein is bound to transferrin receptor 1?

Answer 33

Transferrin

Question 34

How does the HFE protein regulate iron levels?

Answer 34

Iron enters hepatocytes, HFE protein regulates iron absorption by preventing transferring from binding to transferrin 1 Regulates the production of hepcidin, Hepcidin determiens level of iron absorbed from the diet and released from storage sites within the body HFE protein not bound to transferring receptor i ,binds to hepcidin Formation of complex triggers production of hepcidin - inactivated when bound to TF1

Question 35

How does the HFE gene cause hereditary hemochromatosis?

Answer 35

Mutation results in excess iron absorption Humans cannot excrete excess iron, thus accumulates in tissues HFE dysfunction results increased absorption of transferrin

Question 36

What is the prevalence of hereditary hemochromatosis?

Answer 36

1 in 200 homozygous , 0.5% 10% of these have clinically relevant iron accumulation 0.05% have chronic tiredness fatigue - 7% main symtpom in primary care patients]Therefore 1 in 140 have hH in tiredness group